title: HIV rebounds from latently infected cells, rather than from continuing low-level replication.
abstract: Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono- or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing low-level replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.
authors.affiliation: Department of Medicine, Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, CH-8091 Zurich, Switzerland. beda.joos@usz.ch
authors.forename: Beda
authors.initials: B
authors.lastname: Joos
authors.forename: Marek
authors.initials: M
authors.lastname: Fischer
authors.forename: Herbert
authors.initials: H
authors.lastname: Kuster
authors.forename: Satish K
authors.initials: SK
authors.lastname: Pillai
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wong
authors.forename: Jürg
authors.initials: J
authors.lastname: Böni
authors.forename: Bernard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Rainer
authors.initials: R
authors.lastname: Weber
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D002478:Cells, Cultured; D014644:Genetic Variation; D006678:HIV / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D014775:Virus Activation; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D015728:Receptors, HIV